SENP6

Summary

SENP6 (SUMO specific peptidase 6, HGNC:20944) is a protein-coding gene on chromosome 6q14.1, encoding Sentrin-specific protease 6 (Q9GZR1). Protease that deconjugates SUMO1, SUMO2 and SUMO3 from targeted proteins. It is a common-essential gene (DepMap: required in 97.9% of cancer cell lines).

Ubiquitin-like molecules (UBLs), such as SUMO1 (UBL1; MIM 601912), are structurally related to ubiquitin (MIM 191339) and can be ligated to target proteins in a similar manner as ubiquitin. However, covalent attachment of UBLs does not result in degradation of the modified proteins. SUMO1 modification is implicated in the targeting of RANGAP1 (MIM 602362) to the nuclear pore complex, as well as in stabilization of I-kappa-B-alpha (NFKBIA; MIM 164008) from degradation by the 26S proteasome. Like ubiquitin, UBLs are synthesized as precursor proteins, with 1 or more amino acids following the C-terminal glycine-glycine residues of the mature UBL protein. Thus, the tail sequences of the UBL precursors need to be removed by UBL-specific proteases, such as SENP6, prior to their conjugation to target proteins (Kim et al., 2000 [PubMed 10799485]). SENPs also display isopeptidase activity for deconjugation of SUMO-conjugated substrates (Lima and Reverter, 2008 [PubMed 18799455]).

Source: NCBI Gene 26054 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 179 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 97.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_015571

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20944
Approved symbol	SENP6
Name	SUMO specific peptidase 6
Location	6q14.1
Locus type	gene with protein product
Status	Approved
Aliases	SUSP1, KIAA0797
Ensembl gene	ENSG00000112701
Ensembl biotype	protein_coding
OMIM	605003
Entrez	26054

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 29 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000327284, ENST00000370010, ENST00000424947, ENST00000436928, ENST00000447266, ENST00000474906, ENST00000476060, ENST00000483859, ENST00000485497, ENST00000487548, ENST00000493959, ENST00000503501, ENST00000898676, ENST00000898677, ENST00000898678, ENST00000898679, ENST00000898680, ENST00000898681, ENST00000898682, ENST00000898683, ENST00000898684, ENST00000898685, ENST00000938450, ENST00000938451, ENST00000938452, ENST00000938453, ENST00000965011, ENST00000965012, ENST00000965013, ENST00000965014, ENST00000965015, ENST00000965016, ENST00000965017, ENST00000965018, ENST00000965019, ENST00000965020

RefSeq mRNA: 3 — MANE Select: NM_015571 NM_001100409, NM_001304792, NM_015571

CCDS: CCDS43483, CCDS47454, CCDS78158

Canonical transcript exons

ENST00000447266 — 24 exons

Exon	Start	End
ENSE00000797956	75663221	75663518
ENSE00000797957	75666712	75666941
ENSE00000797958	75670553	75670720
ENSE00000797959	75675435	75675468
ENSE00001451483	75715385	75718281
ENSE00001451485	75640684	75640704
ENSE00001863581	75601880	75602576
ENSE00002443458	75677030	75677256
ENSE00002445157	75702645	75703072
ENSE00002479640	75697425	75697517
ENSE00002504846	75678583	75678692
ENSE00002708565	75675860	75676054
ENSE00003480449	75621532	75621625
ENSE00003493682	75634707	75634811
ENSE00003497200	75713513	75713581
ENSE00003502429	75678811	75678927
ENSE00003539584	75659262	75659407
ENSE00003551584	75711328	75711416
ENSE00003601373	75633581	75633726
ENSE00003605460	75709527	75709630
ENSE00003618454	75623900	75623960
ENSE00003619870	75647731	75647801
ENSE00003629096	75695804	75695923
ENSE00003637412	75713675	75713825

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 98.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.5055 / max 258.3651, expressed in 1816 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68622	18.7474	1803
68626	2.4734	1239
68627	1.8973	998
68623	1.7408	1007
68624	1.6316	1010
68628	0.9059	582
68625	0.7861	484
68633	0.5073	205
68629	0.3457	151
68630	0.1853	72

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.77	gold quality
adrenal tissue	UBERON:0018303	97.91	gold quality
ventricular zone	UBERON:0003053	97.83	gold quality
mucosa of stomach	UBERON:0001199	97.73	gold quality
right uterine tube	UBERON:0001302	97.24	gold quality
sural nerve	UBERON:0015488	97.06	gold quality
tendon	UBERON:0000043	96.84	gold quality
left ovary	UBERON:0002119	96.66	gold quality
tibial nerve	UBERON:0001323	96.63	gold quality
ganglionic eminence	UBERON:0004023	96.42	gold quality
right ovary	UBERON:0002118	96.27	gold quality
body of uterus	UBERON:0009853	96.11	gold quality
left lobe of thyroid gland	UBERON:0001120	95.93	gold quality
popliteal artery	UBERON:0002250	95.90	gold quality
tibial artery	UBERON:0007610	95.90	gold quality
thyroid gland	UBERON:0002046	95.87	gold quality
endocervix	UBERON:0000458	95.81	gold quality
ovary	UBERON:0000992	95.71	gold quality
body of pancreas	UBERON:0001150	95.67	gold quality
monocyte	CL:0000576	95.66	gold quality
left uterine tube	UBERON:0001303	95.63	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.61	gold quality
mononuclear cell	CL:0000842	95.56	gold quality
aorta	UBERON:0000947	95.55	gold quality
adenohypophysis	UBERON:0002196	95.45	gold quality
colonic epithelium	UBERON:0000397	95.44	gold quality
right coronary artery	UBERON:0001625	95.44	gold quality
descending thoracic aorta	UBERON:0002345	95.42	gold quality
metanephros cortex	UBERON:0010533	95.40	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.39	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.18
E-ENAD-17	no	1284.94
E-MTAB-6075	no	363.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

131 targeting SENP6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-5680	99.91	69.83	3421

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 18)

• SENP1 localization is influenced by expression and localization of SUMO-1-conjugated target proteins within the cell. (PMID:14563852)
• SUSP1 plays an important role in the control of the transcriptional activity of RXRalpha and thus in the RXRalpha-mediated cellular processes (PMID:16912044)
• We have investigated the specificity of SUSP1 using vinyl sulfone inhibitors and model substrates. SUSP1 has a strong paralogue bias toward SUMO2/3 and acts preferentially on substrates containing three or more SUMO2/3 moieties (PMID:17000875)
• SENP6 and SENP7 exhibit lower rates for processing pre-SUMO1, pre-SUMO2, or pre-SUMO3 in comparison with SENP2 (PMID:18799455)
• Results reveal a novel mechanism whereby the finely balanced activities of SENP6 and RNF4 control vertebrate kinetochore assembly through SUMO-targeted destabilization of inner plate components. (PMID:20212317)
• study of substrate specificity of SENP6; it is also capable of cleaving mixed chains of SUMO-1 and SUMO-2/3; mutation of catalytic cysteine of results in its accumulation in PML NBs; findings indicate SUMO-modified PML is a substrate of SENP6 (PMID:21148299)
• Loop 1 insertion in SENP6 and SENP7 as a platform to discriminate between SUMO1 and SUMO2/3 isoforms in this subclass of the SUMO protease family. (PMID:21878624)
• the structure of SENP2-Loop1 in complex with SUMO2 was solved at 2.15 A resolution, and reveals the details of an interface exclusive to SENP6/7 and the formation of unique contacts between both proteins (PMID:24424631)
• LANA could bind to the promoter region of the SENP6 gene and inhibit SENP6 expression while the regulated SENP6 could in turn modulate the abundance of LANA through desumoylation. (PMID:28615201)
• The authors conclude that SENP6, a factor important for CENP-A maintenance and assembly, functions in protecting a portion of M18BP1 from PIAS4-mediated SUMOylation and subsequent SUMOylation-dependent ubiquitination and degradation. (PMID:30631152)
• SENP6 and FEM1C gene expression in liver transplantation predicts transplantation tolerance. (PMID:30720688)
• SUMO specific peptidase 6 (SENP6) deficient cells are severely compromised for proliferation, accumulate in G2/M and frequently form micronuclei. (PMID:31485003)
• The SUMO Isopeptidase SENP6 Functions as a Rheostat of Chromatin Residency in Genome Maintenance and Chromosome Dynamics. (PMID:31597105)
• SENP6 activity is required throughout the cell cycle, suggesting that a dynamic SUMO cycle underlies a continuous surveillance of the centromere complex. (PMID:31980633)
• Genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma. (PMID:35022408)
• Single Cell RNA-Seq Identifies Immune-Related Prognostic Model and Key Signature-SPP1 in Pancreatic Ductal Adenocarcinoma. (PMID:36292645)
• SENP6-Mediated deSUMOylation of VEGFR2 Enhances Its Cell Membrane Transport in Angiogenesis. (PMID:36768878)
• [Interaction of SENP6 with PINK1 Promotes Temozolomide Resistance in Neuroglioma Cells via Inducing the Mitophagy]. (PMID:38062972)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	senp6b	ENSDARG00000079992
danio_rerio	senp6a	ENSDARG00000102923
mus_musculus	Senp6	ENSMUSG00000034252
rattus_norvegicus	Senp6	ENSRNOG00000024336
drosophila_melanogaster	pira	FBGN0030420
caenorhabditis_elegans		WBGENE00006739

Paralogs (1): SENP7 (ENSG00000138468)

Protein

Protein identifiers

Sentrin-specific protease 6 — Q9GZR1 (reviewed: Q9GZR1)

Alternative names: SUMO-1-specific protease 1, Sentrin/SUMO-specific protease SENP6

All UniProt accessions (6): D6RG09, D6RJH1, Q9GZR1, F8W6D9, H0Y4F4, H0Y8Y8

UniProt curated annotations — full annotation on UniProt →

Function. Protease that deconjugates SUMO1, SUMO2 and SUMO3 from targeted proteins. Processes preferentially poly-SUMO2 and poly-SUMO3 chains, but does not efficiently process SUMO1, SUMO2 and SUMO3 precursors. Deconjugates SUMO1 from RXRA, leading to transcriptional activation. Involved in chromosome alignment and spindle assembly, by regulating the kinetochore CENPH-CENPI-CENPK complex. Desumoylates PML and CENPI, protecting them from degradation by the ubiquitin ligase RNF4, which targets polysumoylated proteins for proteasomal degradation. Also desumoylates RPA1, thus preventing recruitment of RAD51 to the DNA damage foci to initiate DNA repair through homologous recombination.

Subunit / interactions. Interacts with RXRA. Forms a complex with KAT5-TIP60 and UBE2I in response to UV irradiation. Interacts with RPA1 to maintain it in hyposumoylated state during S phase preventing DNA repair initiation.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in reproductive organs, such as testis, ovary and prostate.

Pathway. Protein modification; protein sumoylation.

Similarity. Belongs to the peptidase C48 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9GZR1-1	1	yes
Q9GZR1-2	2

RefSeq proteins (3): NP_001093879, NP_001291721, NP_056386* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003653	Peptidase_C48_C	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR051947	Sentrin-specific_protease	Family

Pfam: PF02902

Enzyme classification (BRENDA):

• EC 3.4.22.B74 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (30 total): modified residue 8, region of interest 6, sequence variant 5, active site 3, sequence conflict 2, compositionally biased region 2, chain 1, cross-link 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZR1-F1	55.33	0.21

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 917; 1030; 765

Post-translational modifications (9): 42, 335, 336, 350, 352, 416, 919, 1111, 628

Mutagenesis-validated functional residues (1):

Position	Phenotype
1030	abolishes enzymatic activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 205 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, RNGTGGGC_UNKNOWN, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, ATGTTAA_MIR302C, GOBP_PEPTIDYL_LYSINE_MODIFICATION, FONTAINE_PAPILLARY_THYROID_CARCINOMA_UP, ROSS_LEUKEMIA_WITH_MLL_FUSIONS, GOBP_REGULATION_OF_SPINDLE_ORGANIZATION, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GOBP_REGULATION_OF_CELL_CYCLE

GO Biological Process (6): proteolysis (GO:0006508), protein sumoylation (GO:0016925), protein desumoylation (GO:0016926), protein modification by small protein removal (GO:0070646), regulation of spindle assembly (GO:0090169), regulation of kinetochore assembly (GO:0090234)

GO Molecular Function (5): SUMO-specific endopeptidase activity (GO:0070139), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
peptidyl-lysine modification	2
regulation of organelle assembly	2
protein metabolic process	1
protein modification by small protein conjugation	1
protein modification by small protein removal	1
protein modification by small protein conjugation or removal	1
spindle assembly	1
regulation of spindle organization	1
regulation of chromosome organization	1
regulation of protein-containing complex assembly	1
kinetochore assembly	1
ubiquitin-like protein-specific endopeptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1870 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SENP6	NKAIN2	Q5VXU1	911
SENP6	SUMO1	P55856	888
SENP6	SUMO2	P55855	884
SENP6	RANGAP1	P46060	848
SENP6	UBE2I	P50550	706
SENP6	SAE1	Q9UBE0	684
SENP6	RNF4	P78317	678
SENP6	SLC25A4	P12235	649
SENP6	SENP8	Q96LD8	643
SENP6	DESI1	Q6ICB0	642
SENP6	UBA2	Q9UBT2	641
SENP6	PIAS4	Q8N2W9	627
SENP6	RPA1	P27694	620
SENP6	PIAS1	O75925	603
SENP6	PIAS2	O75928	591

IntAct

17 interactions, top by confidence:

A	B	Type	Score
PRPF19	AQR	psi-mi:“MI:0914”(association)	0.790
PRPF19	PLRG1	psi-mi:“MI:0914”(association)	0.770
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
SENP6	ZDBF2	psi-mi:“MI:0915”(physical association)	0.400
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
LMNA	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
LMNA	SUPT5H	psi-mi:“MI:2364”(proximity)	0.270
GPKOW	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
HNRNPC	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
QKI	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
SRSF7	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
NPM1	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
SENP6	SCHIP1	psi-mi:“MI:0915”(physical association)	0.000
SENP6	SP1	psi-mi:“MI:0915”(physical association)	0.000
glgB	SENP6	psi-mi:“MI:0915”(physical association)	0.000
TIAM1	SENP6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (61): SUMO1 (Biochemical Activity), SUMO2 (Biochemical Activity), PLA2G2A (Biochemical Activity), SENP6 (Affinity Capture-MS), SENP6 (Affinity Capture-MS), SENP6 (Affinity Capture-MS), SENP6 (Affinity Capture-Western), SENP6 (Reconstituted Complex), SENP6 (Affinity Capture-MS), ZDBF2 (Affinity Capture-MS), SENP6 (Affinity Capture-MS), SENP6 (Affinity Capture-Western), SENP6 (Proximity Label-MS), SENP6 (Proximity Label-MS), SENP6 (Proximity Label-MS)

ESM2 similar proteins: A0A1L8GR68, A2CG63, E6ZGB4, F7AQ22, F8VPQ2, G3V8T1, O75151, O75376, O75475, O88974, O96028, P29374, Q0VEE6, Q0VGB7, Q15047, Q2TB10, Q3TYA6, Q4KKX4, Q4LE39, Q5F363, Q5HYC2, Q5JSH3, Q5R9U6, Q5XJV7, Q5XXA9, Q5ZMU6, Q60974, Q62315, Q66T72, Q6DCQ0, Q6INA9, Q6NVE8, Q6P7W0, Q6P949, Q6P964, Q812D1, Q8BVE8, Q8MJG1, Q8QG78, Q8VBW5

Diamond homologs: A7MBJ2, D3ZF42, O13769, O42957, Q02724, Q6P7W0, Q8BUH8, Q8GYL3, Q8L7S0, Q94F30, Q9BQF6, Q9GZR1, Q0WKV8, Q2PS26, Q8RWN0, O65278, P59110, Q09353, Q5R7K7, Q5RBB1, Q6NXL6, Q8WP32, Q91ZX6, Q96HI0, Q9EP97, Q9EQE1, Q9H4L4, Q9HC62, Q9P0U3, Q09275, Q23238

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 21 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA Splicing - Major Pathway	6	21.9×	1e-05
Dengue Virus-Host Interactions	7	21.3×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
mRNA splicing, via spliceosome	5	22.9×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

179 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	132
Likely benign	9
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

4356 predictions. Top by Δscore:

Variant	Effect	Δscore
6:75621530:A:AG	acceptor_gain	1.0000
6:75621531:G:A	acceptor_loss	1.0000
6:75621531:G:GG	acceptor_gain	1.0000
6:75621531:GCT:G	acceptor_gain	1.0000
6:75621531:GCTT:G	acceptor_gain	1.0000
6:75621531:GCTTT:G	acceptor_gain	1.0000
6:75621619:A:G	donor_gain	1.0000
6:75621623:AGA:A	donor_gain	1.0000
6:75621623:AGAGT:A	donor_loss	1.0000
6:75621624:GA:G	donor_gain	1.0000
6:75621624:GAG:G	donor_gain	1.0000
6:75621626:G:C	donor_loss	1.0000
6:75621626:G:GG	donor_gain	1.0000
6:75621627:T:G	donor_loss	1.0000
6:75623887:A:AG	acceptor_gain	1.0000
6:75623888:T:G	acceptor_gain	1.0000
6:75623893:T:TA	acceptor_gain	1.0000
6:75623895:T:TA	acceptor_gain	1.0000
6:75623896:GTA:G	acceptor_loss	1.0000
6:75623898:A:AG	acceptor_gain	1.0000
6:75623898:AGT:A	acceptor_gain	1.0000
6:75623898:AGTG:A	acceptor_gain	1.0000
6:75623898:AGTGG:A	acceptor_gain	1.0000
6:75623899:G:GC	acceptor_gain	1.0000
6:75623899:GT:G	acceptor_gain	1.0000
6:75623899:GTG:G	acceptor_gain	1.0000
6:75623899:GTGG:G	acceptor_gain	1.0000
6:75623899:GTGGG:G	acceptor_gain	1.0000
6:75633575:TTACA:T	acceptor_loss	1.0000
6:75633576:TACA:T	acceptor_loss	1.0000

AlphaMissense

7432 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:75678813:T:C	L654S	1.000
6:75678821:T:G	Y657D	1.000
6:75678855:T:A	V668D	1.000
6:75678866:G:C	D672H	1.000
6:75678867:A:C	D672A	1.000
6:75678867:A:G	D672G	1.000
6:75678867:A:T	D672V	1.000
6:75678870:T:C	L673P	1.000
6:75678879:T:C	L676P	1.000
6:75678893:T:C	F681L	1.000
6:75678894:T:C	F681S	1.000
6:75678895:T:A	F681L	1.000
6:75678895:T:G	F681L	1.000
6:75678897:T:C	L682S	1.000
6:75678900:A:T	N683I	1.000
6:75678901:T:A	N683K	1.000
6:75678901:T:G	N683K	1.000
6:75678902:G:C	D684H	1.000
6:75678902:G:T	D684Y	1.000
6:75678903:A:C	D684A	1.000
6:75678903:A:G	D684G	1.000
6:75678903:A:T	D684V	1.000
6:75678904:T:A	D684E	1.000
6:75678904:T:G	D684E	1.000
6:75678909:T:A	I686N	1.000
6:75678915:A:T	D688V	1.000
6:75678917:T:C	F689L	1.000
6:75678919:T:A	F689L	1.000
6:75678919:T:G	F689L	1.000
6:75695859:A:C	S711R	1.000

dbSNP variants (sampled 300 via entrez): RS1000000883 (6:75636330 C>T), RS1000031997 (6:75636056 C>A,G,T), RS1000036339 (6:75627667 A>C,G), RS1000052189 (6:75618122 T>G), RS1000062579 (6:75676507 T>G), RS1000101501 (6:75602426 C>G,T), RS1000127566 (6:75671483 G>A), RS1000141532 (6:75642585 C>G,T), RS1000143230 (6:75669212 C>T), RS1000148747 (6:75655008 C>T), RS1000162376 (6:75712833 A>G), RS1000209031 (6:75641352 C>A), RS1000212866 (6:75713072 A>C), RS1000290063 (6:75624087 G>T), RS1000314605 (6:75662939 C>A,T)

Disease associations

OMIM: gene MIM:605003 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000817_110	Height	3.000000e-13
GCST007091_17	Osteoarthritis (hip)	2.000000e-13
GCST008163_218	Height	3.000000e-07
GCST012227_18	Hip circumference adjusted for BMI	6.000000e-09
GCST90020028_605	Hip circumference adjusted for BMI	1.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1741215 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 48,814 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL11417	STREPTONIGRIN	2	43,337
CHEMBL165790	IPRIFLAVONE	2	5,477

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — C48: Ulp1 endopeptidase

Binding affinities (BindingDB)

629 measured of 689 human assays (712 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
4-methoxy-N-(6-methoxy-4H-indeno[1,2-d][1,3]thiazol-2-yl)benzamide	IC50	23 nM
MLS000064750	IC50	113 nM
3-(2-Chloro-acetyl)-8-methyl-1,2,3,3a,4,5-hexahydro-3,10b-diaza-acephenanthrylen-6-one	IC50	348 nM
4-(5-phenyl-1,3-oxazol-2-yl)benzamide	EC50	403 nM
2-(2-chlorophenyl)-5-(4-chlorophenyl)-1,3,4-oxadiazole	EC50	431 nM
MLS000585839	IC50	453 nM
MLS000581513	EC50	702 nM
SMR000186252	IC50	707 nM
5-[(4-methyl-2-nitro-phenoxy)methyl]-3-(2-thienyl)-1,2,4-oxadiazole	EC50	769 nM
5-bromanyl-N-(2,3-dihydro-1H-inden-5-yl)thiophene-2-carboxamide	EC50	772 nM
2-(2-bromophenyl)-5-[(2-fluorophenyl)sulfanylmethyl]-1,3,4-oxadiazole	EC50	818 nM
(6E)-6-[6-amino-4-(ethylamino)-1H-1,3,5-triazin-2-ylidene]-4-chloro-1-cyclohexa-2,4-dienone	EC50	847 nM
(2-phenyl-5,6,7,8-tetrahydrobenzothiopheno[2,3-d]pyrimidin-4-yl)amine	EC50	873 nM
2-[1-(4-methoxyanilino)ethylidene]indene-1,3-dione	EC50	889 nM
MLS000548752	EC50	907 nM
3-[[(4E)-4-(2,4-dimethylphenyl)sulfonylimino-1-keto-2-naphthyl]amino]benzoic acid	IC50	919 nM
N’-[(E)-[4-(diethylamino)-6-oxocyclohexa-2,4-dien-1-ylidene]methyl]-2-methylfuran-3-carbohydrazide	IC50	942 nM
MLS001197729	IC50	950 nM
4-({(4Z)-1-oxo-4-[(phenylsulfonyl)imino]-1,4-dihydronaphthalen-2-yl}amino)benzoic acid	IC50	967 nM
2-[(E)-2-(4-methylphenyl)ethenyl]-1H-quinazolin-4-one	IC50	999 nM
3-(5-p-cumenyltetrazol-2-yl)propionic acid	EC50	1040 nM
5-bromanyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)thiophene-2-carboxamide	EC50	1070 nM
MLS000533921	EC50	1090 nM
4-{5-[(2,4-dichlorophenoxy)methyl]-1,2,4-oxadiazol-3-yl}pyridine	EC50	1120 nM
2-[(2-fluorobenzyl)thio]-5-(4-methylphenyl)-1,3,4-oxadiazole	EC50	1140 nM
MLS001181024	IC50	1220 nM
SMR000269364	IC50	1260 nM
2-[(2-fluorobenzyl)thio]-5-(2-methylphenyl)-1,3,4-oxadiazole	EC50	1270 nM
2-(4-methylphenyl)-6-nitro-indazole	EC50	1290 nM
4-bromanyl-N-(2-phenylsulfanylethyl)benzamide	EC50	1340 nM
1-(1H-benzimidazol-2-yl)-3-methyl-4-phenyl-1H-pyrazol-5-amine	EC50	1420 nM
cid_318105	IC50	1500 nM
cid_3103951	IC50	1590 nM
MLS001173656	IC50	1610 nM
MLS000527241	IC50	1730 nM
cid_2851959	IC50	1840 nM
4-[2-(3-Methyl-pyridin-2-ylamino)-thiazol-4-yl]-benzene-1,3-diol	EC50	1890 nM
5-[(2,4-dimethylphenoxy)methyl]-3-phenyl-1,2,4-oxadiazole	EC50	1960 nM
Acetic acid N-(2,4-dimethyl-phenyl)-N’-[3-oxo-3H-benzo[b]thiophen-(2Z)-ylidene]-hydrazide	EC50	1970 nM
4-Bromo-benzoic acid (1-phenyl-ethylidene)-hydrazide	EC50	2000 nM
(4-amino-3-methyl-5-thieno[2,3-c]isothiazolyl)-(4-methylphenyl)methanone	EC50	2000 nM
(E)-3-(2-methoxy-4-nitro-anilino)-1-(2-thienyl)prop-2-en-1-one	EC50	2050 nM
cid_3746002	IC50	2050 nM
cid_367783	IC50	2080 nM
cid_6040562	IC50	2100 nM
SMR000558842	IC50	2120 nM
4-[2-[[5-(2,5-dichlorophenyl)-2-furanyl]methylidene]hydrazinyl]benzoic acid	IC50	2170 nM
cid_344131	IC50	2230 nM
1-{[(4-fluorobenzoyl)oxy]imino}-1,2,3,4-tetrahydronaphthalene	IC50	2230 nM
MLS000539883	EC50	2230 nM

ChEMBL bioactivities

348 potent at pChembl≥5 of 751 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.73	IC50	186	nM	CHEMBL3196451
6.46	IC50	345	nM	CHEMBL1402456
6.27	IC50	540	nM	CHEMBL1870914
6.24	IC50	580	nM	CHEMBL1316867
6.22	IC50	596	nM	CHEMBL1449923
6.19	IC50	652	nM	CHEMBL1870914
6.18	IC50	660	nM	CHEMBL1891588
6.17	IC50	670	nM	CHEMBL1316867
6.13	IC50	743	nM	CHEMBL1998302
6.13	IC50	742	nM	CHEMBL1879394
6.12	IC50	750	nM	CHEMBL1891206
6.11	IC50	780	nM	CHEMBL1884442
6.10	IC50	802	nM	CHEMBL1417815
6.10	IC50	789	nM	CHEMBL281980
6.10	IC50	787	nM	CHEMBL1506796
6.10	IC50	790	nM	CHEMBL1871228
6.09	IC50	819	nM	CHEMBL1969046
6.09	IC50	805	nM	CHEMBL205040
6.08	IC50	838	nM	CHEMBL1477061
6.08	IC50	830	nM	CHEMBL1884495
6.07	IC50	849	nM	CHEMBL3191962
6.06	IC50	869	nM	CHEMBL1869875
6.04	IC50	905	nM	CHEMBL1586985
6.03	IC50	936	nM	CHEMBL1471498
6.03	IC50	927	nM	CHEMBL1525161
6.03	IC50	938	nM	CHEMBL1871228
6.02	IC50	961	nM	CHEMBL1421255
6.01	IC50	984	nM	CHEMBL1376622
6.01	IC50	986	nM	CHEMBL1575869
6.01	IC50	970	nM	CHEMBL1869393
5.97	IC50	1080	nM	CHEMBL1475128
5.96	IC50	1110	nM	CHEMBL1542328
5.94	IC50	1150	nM	CHEMBL1967857
5.94	IC50	1150	nM	CHEMBL1869393
5.94	IC50	1160	nM	CHEMBL1302779
5.93	IC50	1170	nM	CHEMBL1613216
5.92	IC50	1190	nM	CHEMBL1891206
5.92	IC50	1200	nM	CHEMBL1319405
5.91	IC50	1220	nM	CHEMBL1888516
5.90	IC50	1260	nM	CHEMBL1418096
5.90	IC50	1260	nM	CHEMBL1577231
5.89	IC50	1300	nM	CHEMBL1885269
5.89	IC50	1300	nM	CHEMBL1877777
5.88	IC50	1310	nM	CHEMBL3195102
5.87	IC50	1350	nM	CHEMBL1319405
5.85	IC50	1420	nM	CHEMBL1988780
5.85	IC50	1400	nM	CHEMBL1584379
5.85	IC50	1400	nM	CHEMBL1577231
5.85	IC50	1400	nM	CHEMBL1302779
5.85	IC50	1400	nM	CHEMBL1878061

PubChem BioAssay actives

3 with measured affinity, of 13 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[3-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-2-[[2-(4-hydroxy-3-nitrophenyl)acetyl]amino]-4-methylpentanoyl]amino]pentanoyl]amino]acetyl]amino]-2-oxopropyl] anthracene-9-carboxylate	1799555: Fluorogenic Assay from Article 10.1016/j.chembiol.2011.05.008: “Development of small molecule inhibitors and probes of human SUMO deconjugating proteases.”	ic50	4.2000	uM
5-amino-6-(7-amino-6-methoxy-5,8-dioxoquinolin-2-yl)-4-(2-hydroxy-3,4-dimethoxyphenyl)-3-methylpyridine-2-carboxylic acid	1859340: Inhibition of human SENP6 using AMC-tagged SUMO1 as substrate incubated for 10 mins by fluorescence based analysis	ic50	5.2000	uM

CTD chemical–gene interactions

49 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, decreases methylation, affects cotreatment	9
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
trichostatin A	affects expression, decreases expression	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
butyraldehyde	decreases expression	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
deguelin	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
(+)-JQ1 compound	affects expression, increases reaction	1
Irinotecan	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	decreases expression	1
Panobinostat	affects expression, increases reaction	1
Acetaminophen	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 3 functional, 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1738502	Functional	PUBCHEM_BIOASSAY: Dose Response confirmation of uHTS for inhibitors of Sentrin-specific protease 6 (SENP6) using a Luminescent assay. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID2575, AID2582, AID2599]	PubChem BioAssay data set
CHEMBL4372623	Binding	Inhibition of recombinant His6-tagged SENP6 catalytic domain (628 to 1112 residues) (unknown origin) at 1 to 25 uM using SUMO2-modified RanGap1 as substrate preincubated for 30 mins followed by substrate addition and measured after 10 mins	Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.